Pharmacogenetics of folate-related drug targets in cancer treatment

Abstract

Folate metabolism is the target of two major drug groups: folate antagonists (for example, methotrexate) and thymidylate synthase inhibitors (for example, 5-fluorouracil). These agents are used in the treatment of cancer, as well as for other conditions, such as rheumatoid arthritis. High-dose cancer treatment protocols can induce a state of acute folate depletion which may lead to significant treatment-related toxicity. Polymorphisms in folate-metabolizing enzymes may modify the therapeutic effectiveness and toxicity of these drugs. This review briefly summarizes the drugs targeting the folate pathway and describes common polymorphisms in folate-metabolizing enzymes and transport proteins. Pharmacogenetic studies investigating folate-related drug targets in the treatment of colorectal cancers and hematologic malignancies will subsequently be discussed. Findings to date illustrate a potential for targeting therapy based on patients' genotypes, in order to improve outcomes and reduce toxicity. However, larger, well-designed studies are needed to confirm these early findings.